In some clinical situations it is desirable to provide a portion of a living body, such as a human body, with a drug over an extended time period (e.g., days, weeks, or months). For example, it may be desirable to provide a broken, or diseased, portion of mammalian bone with a growth factor, that promotes new bone growth, during the process of bone healing. One way to provide the drug is to implant a drug delivery composition at the desired location in the living body. Some drug delivery compositions are biodegradable, exist as a gel at the temperature of the living body, but exist as a liquid below the temperature of the living body. Drug molecules can be incorporated into these compositions in their liquid form, and the compositions can thereafter be introduced into a living body where they form a gel that is degraded by the body over time, thereby releasing the drug molecules.
Synthetic polymers such as polyethylene glycol, poly(lactic acid) (PLA), and PEG-PLGA-PEG have been used as thermoreversible drug delivery systems (Jeong, B. et al., Nature 388:860 (1997); Jeong, B., et al., Macromolecules 32:7064 (1999); Jeong, B., et al., J. Biomed. Mater. Res. 50:171 (2000)). Natural polymers are typically more desirable than synthetic polymers for biomedical applications because of their biocompatibility and biodegradability. (Jeong, B., and A. Gutowska, Trends Biotechnol. 20:360 (2002); Chenite, A., et al., Biomaterials 21:2155 (2000)). For example, Chenite et al. (Biomaterials 21:2155 (2000)) developed a thermoreversible gel, composed of chitosan and glycerol-2-phosphate salts, that gels at a temperature of about 37° C., or above, depending on the amount of the salts present in the composition. In the practice of the Chenite et al. technology, the chitosan solution had to be prepared in dilute acid in order to dissolve the chitosan. Consequently, the chitosan solution had an acidic pH that is irritating to living tissue. Additionally, excess sodium glycerol phosphate (β-GP) salt was required to gel the chitosan solution. The excess β-GP salt may be harmful if it is absorbed by living tissue.
A need remains, therefore, for drug delivery compositions, made from biocompatible natural, or synthetic, polymers, that are biodegradable and that exist as a liquid below the temperature of a recipient living body, and as a gel at the temperature of the recipient living body. The liquid phase of the compositions can be loaded with drug molecules, and thereafter be introduced into a living body where they form a gel that is degraded and releases the drug over time.